Abstract
Secondary active transporters (SATs) require large protein conformational changes, which some believe follow the alternating access model. The structure of each characteristic conformational state is important for understanding the complete substrate transport process. However, the structure of certain state(s) can be very difficult to obtain by experiment, while certain enhanced simulation techniques may provide an approach to predict unknown structures. Self-guided Langevin dynamics (SGLD) (Chem. Phys. Lett., 381: 512-518) simulations allows proteins to overcome energy barriers and thus it can be used to search the structures of all the conformational states efficiently by enhancing the conformational sampling of low frequency motion. SGLD accelerates the conformational change while preserves the conformational distribution well. Therefore, this method is applied to study a SAT - lactose permease of E.coli. (LacY), which belongs to major facilitator superfamily (MFS). LacY structures of the cytoplasmic-open and occluded-like structure have been determined. To search the periplasmic-open LacY, SGLD simulations are performed with inward-facing LacY as initial structure, with different residues protonated, with and without ββ-(Galp)2, in the implicit membrane and in an explicit membrane in the NVT ensemble (available recently). The SGLD parameters adjusted are guiding factor and friction factor to control guiding force, and also local average time to set the boundary of low frequency motion to enhance. The preliminary broad SGLD parameters sweep are applied to find reasonable parameter set range for sampling protein structures. Then, a fine parameter sweep is applied to obtain the optimized structure. The effect of each parameter set, the protonation states, and presence of sugar on LacY residue distances and pore radii will be presented. These optimal SGLD parameter values may be applied to study conformational changes of other similar SAT proteins.
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